New Mutations Exhibiting SARS-CoV-2 Spike Deletion ΔH69/ΔV70 That Can Escape Immune Recognition Fast Becoming Prevalent

A new SARS-CoV-2 mutation strain that exhibits spike deletion mutations ΔH69/ΔV70 is fast becoming prevalent and is not only able  only escape human host immune recognition but could well also be resistant to various types of antibodies according to a new research by scientists from the University College London, University of Cambridge and the University of Glasgow Centre for Virus Research.


 
SARS-CoV-2 Spike amino acid replacements in the receptor binding domain (RBD) occur relatively frequently and some have a consequence for immune recognition.
 
The study team reports recurrent emergence and significant onward transmission of a six nucleotide deletion in the Spike gene, which results in loss of two amino acids: ΔH69/ΔV70. Of particular note this deletion often co-occurs with the receptor binding motif amino acid replacements N501Y, N439K and Y453F.
 
In addition, the study team reports a sub-lineage of over 350 sequences bearing seven spike mutations across the RBD (N501Y, A570D), S1 (ΔH69/V70) and S2 (P681H, T716I, S982A and D1118H) in England. Some of these mutations have possibly arisen as a result of the virus evolving from immune selection pressure in infected individuals.
 
Enhanced surveillance for the ΔH69/ΔV70 deletion with and without RBD mutations should be considered as a priority.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2020.12.14.422555v2
 
From the start of the COVID 19 pandemic, it has been established that the SARS-CoV-2 gains entry to the target host cell via its spike glycoprotein.
 
Numerous mutations have since occurred in this viral protein, some with the ability to alter the antibody recognition site.
 
This study warns about a pair of linked mutations, ΔH69/ΔV70, which has shown repeated emergence and transmission.
 
Interestingly some of these escape mutations emerge following convalescent plasma use showing that its truly mankind that is helping to give rise to newer dangerous mutations.
 
Typically, the viral spike protein attaches to the host cell receptor, angiotensin-converting enzyme 2 (ACE2), found in many human tissues. Though the spike protein is central to viral entry, its receptor-binding domain (RBD) has remarkable mutational tolerance.
 
The non-proper increasing use of convalescent plasma or CP has led to the emergence of spike ΔH69/ΔV70 and D796H variants. These mutations in the spike N-terminal domain (NTD) may allow escape from neutralizing anti-NTD antibodies in CP bu t without impact on infectivity.
 
Fortunately with the enormous scale on which SARS-CoV-2 genome sequencing is occurring at present, it has become possible to examine multiple parameters for their correlation with increased infectivity and transmissibility.
 
This new study aimed to explore the underlying situation in which the ΔH69/ΔV70 mutation arose, using data from the Global Initiative on Sharing All Influenza Data (GISAID) data.
 
The study team found that of the available data, about 2.5%, or 3,000 sequences, contained this deletion, though most of them were necessarily from Europe since this was the origin of the majority of GISAID sequences. The presence of the mutation in many different lineages reflected its independent emergence at least five times.
 
Initially occurring independently in Thailand and Germany, as far back as January 2020, its prevalence went up after a few months, from August 2020. In some variants, this double mutation was present in isolation, and in others, they were present along with other RBD mutations.
 
The study team created a homology model of the spike NTD with the double mutation. They observed that in this model, the mutation led to a shift in the positions of several residues, resulting in a predicted change in the conformation of a protruding loop made up of amino acids from positions 69-76, by pulling it into the NTD.
 
The team looked at viral lineages with a high frequency of spike mutations, especially in combination with N439K. The latter may prevent neutralization by some anti-RBD monoclonal antibodies (mAbs), despite showing an intact affinity for ACE2. The frequency of the double mutation increased markedly from August onwards, in combination with N439K.
 
Alarmingly by November, the number of sequences with all three mutations was double that of sequences containing only N439K.
 
Yet another cluster showed the double deletion emerging in a lineage containing Y453F, an RBD mutation that resulted in increased binding affinity for the ACE2 receptor. This was again associated with reduced neutralization by COVID-19 antiserum. This has been found only in Danish sequences so far.
 
Importantly another RBD mutation N501Y has been associated with the same double deletion. Its location raises the possibility that it may be an escape mutation from antibodies like CoV2-2499. Moreover, the passage of SARS-CoV-2 in mice led to the emergence of the single mutation with an increased pathogenic effect.
 
Significantly, sequences with N501Y alone have been found in the UK and Brazil from April onwards. However, the number of sequences with N501Y along with the double deletion increased following their emergence in the UK in September 2020. At present, they exceed the number of sequences containing the single mutation.
 
It should be noted that this especially relates to a sub-lineage containing ~350 sequences, with six novel mutations involving the RBD (including N501Y), spike S2 subunit, and the double deletion. This long-branch mutation set could either have come from an area with very little surveillance or from a chronically infected individual, where the virus persisted and replicated in the host for a long period.
 
Most importantly multiple clusters of virus variants have emerged in several episodes. In all these cases, the double deletion has been found to emerge in association with a mutation of the RBD that reduces receptor binding by mAbs and is increasing in prevalence. NTD deletions have the potential to increase viral transmissibility.
 
It was found that the double deletion affecting an exposed surface which may enable the variant to escape immune recognition. This could be by shifting linkages between the spike subunits and altering RBD orientation, thus impacting viral spread and infectivity.
 
The only measures to prevent such escape mutations from hampering containment strategies are to take increased care of non-pharmaceutical interventions and speed up drug and therapeutic research for effective antivirals.
 
Also importantly the development of rapid diagnostic tests for the double deletion will be important in signaling the emergence of antibody escape mutations and thus enabling global monitoring of virus adaptation.
 
The study team concluded, “The finding of a sub-lineage of over 350 sequences bearing seven spike mutations across the RBD (N501Y, A570D), S1 (H69/V70) and S2 (P681H, T716I, S982A and D1118H) in England requires careful monitoring. The detection of a high number of novel mutations suggests this lineage has either been introduced from a geographic region with very poor sampling or viral evolution may have occurred in a single individual in the context of a chronic infection.”
 
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